Intracellular domain of epithelial cell adhesion molecule induces Wnt receptor transcription to promote colorectal cancer progression.

BACKGROUND: Epithelial cell adhesion molecule (EpCAM) has been widely studied as a tumor antigen due to its expression in varieties of solid tumors. Moreover, the glycoprotein contributes to critical cancer-associated cellular functionalities via its extracellular (EpEX) and intracellular (EpICD) domains. In colorectal cancer (CRC), EpCAM has been implicated in the Wnt signaling pathway, as EpICD and ß-Catenin are coordinately translocated to the nucleus. Once in the nucleus, EpICD transcriptionally regulates EpCAM target genes that; however, remains unclear whether Wnt signaling is modulated by EpICD activity. METHODS: Patient-derived organoids (PDOs), patient-derived xenografts (PDXs), and various CRC cell lines were used to study the roles of EpCAM and EpICD in Wnt receptor expression. Fluorescence and confocal microscopy were used to analyze tumors isolated from PDX and other xenograft models as well as CRC cell lines. EpCAM signaling was intervened with our humanized form of EpCAM neutralizing antibody, hEpAb2-6. Wnt receptor promoters under luciferase reporters were constructed to examine the effects of EpICD. Luciferase reporter assays were performed to evaluate promoter, γ-secretase and Wnt activity. Functional assays including in vivo tumor formation, organoid formation, spheroid and colony formation experiments were performed to study Wnt related phenomena. The therapeutic potential of EpCAM suppression by hEpAb2-6 was evaluated in xenograft and orthotopic models of human CRC. RESULTS: EpICD interacted with the promoters of Wnt receptors (FZD6 and LRP5/6) thus upregulated their transcriptional activity inducing Wnt signaling. Furthermore, activation of Wnt-pathway-associated kinases in the ß-Catenin destruction complex (GSK3ß and CK1) induced γ-secretase activity to augment EpICD shedding, establishing a positive-feedback loop. Our hEpAb2-6 antibody blocked EpICD-mediated upregulation of Wnt receptor expressions and conferred therapeutic benefits in both PDX and orthotopic models of human CRC. CONCLUSIONS: This study uncovers relevant functions of EpCAM where Wnt receptors are upregulated via the transcriptional co-factor activity of EpICD. The resultant enhancement of Wnt signaling induces γ-secretase activity further stimulating EpICD cleavage and its nuclear translocation. Our humanized anti-EpCAM antibody hEpAb2-6 blocks these mechanisms and may thereby provide therapeutic benefit in CRC.

The survival outcome differs between left-sided colon cancer and middle/low rectal cancer after colorectal hepatic metastasectomy.

BACKGROUND: The clinical outcomes between left-sided colon cancer and middle/low rectal cancer seem to be different. This study aimed to examine the effect of primary tumor location regarding the left-sided colon and middle/low rectum on the overall survival (OS) of patients who underwent colorectal hepatic metastasectomy. METHODS: Patients who underwent colorectal hepatic metastasectomy were retrospectively enrolled. Patients were classified into 2 groups according to the primary tumor location (left-sided colon and middle/low rectum). Categorical variables were compared using the chi-square test or Fisher exact test, and continuous variables were analyzed using the Student t test. Survival was analyzed using the Kaplan-Meier method and log-rank test. The prognostic factors were analyzed by univariate and multivariate analyses using Cox proportional hazards regression models. RESULTS: Overall, 365 patients were enrolled. Patients with left-sided colon cancer had significantly better OS than those with middle/low rectal cancer (hazard ratio [HR], 0.725; P = .018), with median OS estimates of 48 and 38 months, respectively. In the subgroup analysis of RAS mutations, patients with left-sided colon cancer had significantly prolonged OS compared with those with middle/low rectum cancer (HR, 0.608; P = .034), with median OS estimates of 49 and 26 months, respectively. This observation was limited to patients with RAS mutations. CONCLUSION: According to our findings, patients with middle/low rectal cancer had poorer survival outcome and should not be categorized together with patients with left-sided colon cancer in terms of OS after colorectal hepatic metastasectomy.

Surgical strategy for colorectal cancer with synchronous liver and extrahepatic metastases: A scoring system and decision tree model.

BACKGROUND: The role of hepatectomy in a specific group of patients with synchronous colorectal cancer with liver metastases (SCRLM) and synchronous extrahepatic disease (SEHD) is still unclear. The aim of this study was to evaluate the efficacy of liver surgery and define the selection criteria for surgical candidates in patients with SCRLM + SEHD. METHODS: Between July 2007 and October 2018, 475 patients with colorectal cancer with liver metastases (CRLM) who underwent liver resection were retrospectively reviewed. Sixty-five patients with SCRLM + SEHD were identified and included in the study. Clinical pathological data of these patients were analyzed to evaluate the influence on survival. Important prognostic factors were identified by univariate and multivariate analyses. The risk score system and decision tree analysis were generated according to the important prognostic factors for better patient selection. RESULTS: The 5-year survival rate of patients with SCRLM + SEHD was 21.9%. The most important prognostic factors were SCRLM number of more than five, site of SEHD other than the lung only, inability to achieve SCRLM + SEHD R0 resection, and BRAF mutation of cancer cells. The proposed risk score system and decision tree model easily discriminated between patients with different survival rates and identified the profile of suitable surgical patients. CONCLUSION: Liver surgery should not be a contraindication for patients with SCRLM + SEHD. Patients with complete SCRLM + SEHD R0 resection, SCRLM number less than or equal to five, SEHD confined to the lung only, and wild-type BRAF could have favorable survival outcomes. The proposed scoring system and decision tree model may be beneficial to patient selection in clinical use.

Modeling the survival of colorectal cancer patients based on colonoscopic features in a feature ensemble vision transformer.

The prognosis of patients with colorectal cancer (CRC) mostly relies on the classic tumor node metastasis (TNM) staging classification. A more accurate and convenient prediction model would provide a better prognosis and assist in treatment. From May 2014 to December 2017, patients who underwent an operation for CRC were enrolled. The proposed feature ensemble vision transformer (FEViT) used ensemble classifiers to benefit the combinations of relevant colonoscopy features from the pretrained vision transformer and clinical features, including sex, age, family history of CRC, and tumor location, to establish the prognostic model. A total of 1729 colonoscopy images were enrolled in the current retrospective study. For the prediction of patient survival, FEViT achieved an accuracy of 94 % with an area under the receiver operating characteristic curve of 0.93, which was better than the TNM staging classification (90 %, 0.83) in the experiment. FEViT reduced the limited receptive field and gradient disappearance in the conventional convolutional neural network and was a relatively effective and efficient procedure. The promising accuracy of FEViT in modeling survival makes the prognosis of CRC patients more predictable and practical.

Anti-VEGF Therapy Possibly Extends Survival in Patients With Colorectal Brain Metastasis by Protecting Patients From Neurologic Disability.

BACKGROUND: Colorectal brain metastases (CBMs) are rare with poor prognosis. There is still no standard systemic treatment for multiple or unresectable CBM. our study aimed to explore the impact of anti-VEGF therapy on overall survival, brain-specific disease control, and neurologic symptom burden in patients with CBM. METHODS: A total of 65 patients with CBM under treatment were retrospectively enrolled and divided into anti-VEGF based systemic therapy or non-anti-VEGF based therapy. A total of 25 patients who received at least 3 cycles of anti-VEGF agent and 40 patients without anti-VEGF therapy were analyzed by endpoints of overall survival (OS), progression-free survival (PFS), intracranial PFS (iPFS) and neurogenic event-free survival (nEFS). Gene expression in paired primary metastatic colorectal cancer (mCRC), liver, lung and brain metastasis from NCBI data was analyzed using top Gene Ontology (GO) and cBioPortal. RESULTS: Patients who treated with anti-VEGF therapy had significantly longer OS (19.5 vs. 5.5 months, P = .009), iPFS (14.6 vs. 4.1 months, P < .001) and nEFS (17.6 vs. 4.4 months, P < .001). Patients who received anti-VEGF therapy beyond any disease progression presented with superior OS (19.7 vs. 9.4 months, P = .039). Top GO and cBioPortal analysis revealed a stronger molecular function of angiogenesis in intracranial metastasis. CONCLUSIONS: Anti-VEGF based systemic therapy showed favorable efficacy that was reflected in longer overall survival, iPFS and NEFS in patients with CBM.

Longitudinal neutralizing antibody responses after SARS-CoV-2 infection: A convalescent cohort study in Taiwan.

BACKGROUND: Understanding the neutralizing antibody (NAb) titer against COVID-19 over time is important to provide information for vaccine implementation. The longitudinal NAb titer over one year after SARS-CoV-2 infection is still unclear. The purposes of this study are to evaluate the duration of the neutralizing NAb titers in COVID-19 convalescents and factors associated with the titer positive duration. METHODS: A cohort study followed COVID-19 individuals diagnosed between 2020 and 2021 May 15th from the COVID-19 database from the Taiwan Centers for Disease Control. We analyzed NAb titers from convalescent SARS-CoV-2 individuals. We used generalized estimating equations (GEE) and a Cox regression model to summarize the factors associated with NAb titers against COVID-19 decaying in the vaccine-free population. RESULTS: A total of 203 convalescent subjects with 297 analytic samples were followed for a period of up to 588 days. Our study suggests that convalescent COVID-19 in individuals after more than a year and four months pertains to only 25% of positive titers. The GEE model indicates that longer follow-up duration was associated with a significantly lower NAb titer. The Cox regression model indicated the disease severity with advanced condition was associated with maintaining NAb titers (adjusted hazard ratio: 2.01, 95% CI: 1.11-3.63) and that smoking was also associated with higher risk of negative NAb titers (adjusted hazard ratio: 0.55, 95% CI: 0.33-0.92). CONCLUSIONS: Neutralizing antibody titers diminished after more than a year. The antibody titer response against SARS-CoV-2 in naturally convalescent individuals provides a reference for vaccinations.

The Negative Prognostic Impact of Lymph Node Skip Metastasis in Stage III Colon Cancer With pN1 Disease: A Single-Center and Retrospective Cohort Study.

BACKGROUND: Lymph node skip metastasis is a subgroup of lymph node metastatic patterns with low incidence in node-positive colon cancer. Its clinical significance is still unclear. OBJECTIVE: This study aimed to investigate the prognostic impact of lymph node skip metastasis in stage III colon cancer. DESIGN: This is a retrospective observational analysis. SETTINGS: The study was conducted at the Taipei Veterans General Hospital. PATIENTS: This study included patients with stage III colon cancer who underwent D3 lymphadenectomy between 2006 and 2015. MAIN OUTCOME MEASURES: The patients were divided into a lymph node skip metastasis-positive group and a negative group. Recurrence-free survival and overall survival were compared using Kaplan-Meier curves and log-rank test. Cox regression was applied to identify related risk factors influencing survival. RESULTS: A total of 461 patients were reviewed, and lymph node skip metastasis-positive patients represented 13.2% of our sample. Patients with lymph node skip metastasis tended to present with a higher proportion of right-sided cancer, lower positive lymph nodes, lower lymph node ratio, and higher mean BMI. Liver recurrence was more prevalent in the lymph node skip metastasis group ( p = 0.028) than in the negative group. The presence of lymph node skip metastasis was a negative prognostic factor for 5-year recurrence-free survival (51.4% vs 68.7%; p = 0.002) and 5-year overall survival (66.4% vs 80.4%; p = 0.024) in Kaplan-Meier curves and multivariate Cox regression. Subgroup analysis revealed the survival significance of recurrence-free survival ( p = 0.001) and overall survival ( p = 0.011) in lymph node skip metastasis with pN1 disease. LIMITATIONS: This study was limited by its retrospective design, single-center nature, and sampling error. CONCLUSIONS: Lymph node skip metastasis is an independent negative prognostic factor in stage III colon cancer with pN1 disease. More intensive surveillance may be necessary for patients of this subgroup. See Video Abstract at https://links.lww.com/DCR/C60 . IMPACTO PRONSTICO NEGATIVO DE LAS METSTASIS DISCONTNUAS GANGLIONARES LINFTICAS EN CASOS DE CNCER DE COLON ESTADIO III CON ENFERMEDAD PN ESTUDIO DE COHORTES RETROSPECTIVO MONOCENTRICO: ANTECEDENTES:Las metástasis discontínuas ganglionares linfáticas, son un subgrupo de patrones metastásicos en los ganglios linfáticos con baja incidencia en el cáncer de colon con nódulos positivos. Su significado clínico aún no está claro.OBJETIVO:Estudio que tiene por objetivo el investigar el impacto pronóstico de las metástasis discontínuas de los ganglios linfáticos en el cáncer de colon de estadio III.DISEÑO:Análisis observacional retrospectivo.AJUSTES:El estudio se realizó en el Hospital General de Veteranos de Taipei.PACIENTES:Pacientes con cáncer de colon en estadio III que se sometieron a linfadenectomía D3 entre 2006 y 2015.PRINCIPALES MEDIDAS DE RESULTADO:Los pacientes se dividieron en un grupo positivo de metástasis discontínuas en los ganglios linfáticos y un otro grupo negativo. La sobrevida libre de recidiva y la sobrevida global, fueron comparadas mediante las curvas de Kaplan-Meier y la prueba de rango logarítmico. Se aplicó la regresión de Cox para identificar los factores de riesgo relacionados que influyeron en la sobrevida.RESULTADOS:Se revisaron un total de 461 casos, donde los pacientes positivos con metástasis en los ganglios linfáticos representaron el 13,2% de nuestra muestra. Los pacientes con metástasis discontínuas ganglionares linfáticas tendían a presentar una mayor proporción de cáncer localizado en el lado derecho del colon, presentar un menor numéro de ganglios linfáticos positivos y una proporción menor de ganglios linfáticos con un IMC promedio más alto. Las recidivas hepáticas fueron más prevalentes en el grupo de metástasis discontínuas ganglionares linfáticas ( p = 0,028) que en el grupo negativo. La presencia de metástasis discontínuas ganglionares linfáticas fué un factor de pronóstico negativo en la sobrevida libre de recidiva a 5 años (51,4% frente a 68,7%, p = 0,002) y la sobrevida general a 5 años (66,4% frente a 80,4%, p = 0,024) evaluada por las curvas de Kaplan-Meier y la regresión multivariada de Cox. El análisis de subgrupos reveló la importancia de la sobrevida libre de recidiva ( p = 0,001) y la sobrevida general ( p = 0,011) en los casos con metástasis discontínuas ganglionares linfáticas con enfermedad pN1.LIMITACIONES:Diseño retrospectivo, naturaleza de centro único y error de muestreo.CONCLUSIONES:Las metástasis discontínuas ganglionares linfáticas son un factor pronóstico negativo independiente en los casos de cáncer de colon estadio III con enfermedad pN1. Tal vez sea necesaria una mayor vigilancia de los pacientes en este subgrupo.Consulte Video Resumen en https://links.lww.com/DCR/C60 . (Traducción-Dr. Xavier Delgadillo ).

Clinical outcome of local treatment and radical resection for pT1 rectal cancer.

BACKGROUND: Rectal cancer is mainly cured by radical resection with neoadjuvant chemoradiation or adjuvant chemotherapy. Pathological T1 lesions can be managed by local treatment and radiotherapy thereafter. Lower morbidity is the key benefit of these local treatments. Since nodal metastasis is important for staging, radical resection (RR) is suggested. Rectal cancer has higher surgical morbidity than colon cancer; local treatment has been the preferred choice by patients. METHODS: We retrospectively enrolled data of 244 patients with pT1 rectal adenocarcinoma. A total of 202 patients (82.8%) underwent RR, including low anterior resection (LAR) and abdomino-perineal resection (APR), and 42 patients (17.2%) underwent LT, including transanal excision and colonoscopic polypectomy. RESULTS: In our study, seven patients (16.7%) had loco-regional recurrence and distant metastasis from the LT group while eight patients (4.0%) had distant metastasis without loco-regional recurrence from the RR group. The lymph node metastasis rate in RR group was 8.4%. Forty-seven patients (24.2%) underwent LAR with temporary stoma, and its reversal rate was 100%. In the RR group, postoperative complication rate was 10.4% with a mortality rate of 0.5%. Recurrence-free survival (RFS) was 95.7% for RR and 80.2% for LT (P = 0.001), and overall survival (OS) was 93.7% for RR and 70.0% for LT (P = 0.001). CONCLUSION: This study found that RFS and OS in patients of pT1 rectal adenocarcinoma that had received RR were better than receiving LT. Further adjuvant chemotherapy was possible for some RR patients. A higher recurrence rate after LT must be balanced against the morbidity and mortality associated with RR.

Patient-Derived Organoid Serves as a Platform for Personalized Chemotherapy in Advanced Colorectal Cancer Patients.

Background: Addition of oxaliplatin to adjuvant 5-FU has significantly improved the disease-free survival and served as the first line adjuvant chemotherapy in advanced colorectal cancer (CRC) patients. However, a fraction of patients remains refractory to oxaliplatin-based treatment. It is urgent to establish a preclinical platform to predict the responsiveness toward oxaliplatin in CRC patients as well as to improve the efficacy in the resistant patients. Methods: A living biobank of organoid lines were established from advanced CRC patients. Oxaliplatin sensitivity was assessed in patient-derived tumor organoids (PDOs) in vitro and in PDO-xenografted tumors in mice. Based on in vitro oxaliplatin IC50 values, PDOs were classified into either oxaliplatin-resistant (OR) or oxaliplatin-sensitive (OS) PDOs. The outcomes of patients undergone oxaliplatin-based treatment was followed. RNA-sequencing and bioinformatics tools were performed for molecular profiling of OR and OS PDOs. Oxaliplatin response signatures were submitted to Connectivity Map algorithm to identify perturbagens that may antagonize oxaliplatin resistance. Results: Oxaliplatin sensitivity in PDOs was shown to correlate to oxaliplatin-mediated inhibition on PDO xenograft tumors in mice, and parallelled clinical outcomes of CRC patients who received FOLFOX treatment. Molecular profiling of transcriptomes revealed oxaliplatin-resistant and -sensitive PDOs as two separate entities, each being characterized with distinct hallmarks and gene sets. Using Leave-One-Out Cross Validation algorithm and Logistic Regression model, 18 gene signatures were identified as predictive biomarkers for oxaliplatin response. Candidate drugs identified by oxaliplatin response signature-based strategies, including inhibitors targeting c-ABL and Notch pathway, DNA/RNA synthesis inhibitors, and HDAC inhibitors, were demonstrated to potently and effectively increase oxaliplatin sensitivity in the resistant PDOs. Conclusions: PDOs are useful in informing decision-making on oxaliplatin-based chemotherapy and in designing personalized chemotherapy in CRC patients.

A Long-Term and Large-Scale Real-World Study in Taiwan: Efficacy of Target Therapy in Stage IV Colorectal Cancer.

This study expands the understanding of the role of target therapy in improving survival of patients with mCRC based on real-world study results. These data represent potential survival outcomes of Taiwanese patients with mCRC in clinical practice. CRC is the most commonly diagnosed cancer and the third leading cause of cancer-related death in Taiwan. The aim of this study was to evaluate the efficacy of target therapy in combination with chemotherapy for mCRC in Taiwan. This was a real-world, retrospective, observational study in patients diagnosed with mCRC (N=1583). A total of 792 patients received chemotherapy plus target therapy (anti-EGFR therapy, n=180; anti-VEGF therapy, n=612) and 791 patients who received chemotherapy alone. Overall survival (OS) and progression-free survival (PFS) were examined. For RAS wild-type patients, the median OS (mOS) was 34.3 months in the EGFR L (left-sided colon) group, 27.3 months in the VEGF L group, 18.4 months in VEGF R (right-sided colon) group, and 13.8 months in EGFR R group (P<0.001). Median PFS (mPFS) was 9.8 months in the EGFR L group, 8.9 months in the VEGF L group, 6.8 months in VEGF R group, and 5.8 months in EGFR R group. In patients with a RAS mutation, mOS was 25.4 months in the VEGF L group and 19.4 months in the VEGF R group (P=0.167). Judicious treatment allocation in Taiwanese patients with mCRC can result in an mOS of 34.3 months using cetuximab plus chemotherapy for left-sided tumors. An mOS of 48.5 months can be achieved using cetuximab plus chemotherapy in the neoadjuvant setting in mCRC patients with left-sided tumors. This study expands our understanding of the role of target therapy in improving survival of mCRC patients based on real-world study results.

Three-dimensional versus conventional two-dimensional laparoscopic colectomy for colon cancer: A 3-year follow-up study.

Background: Three-dimensional (3D) laparoscopy was developed to overcome the drawbacks of two-dimensional (2D) laparoscopy, namely lack of depth perception. However, the benefit of 3D laparoscopy in colorectal surgery is inconclusive. Here, we compare the 3-year follow-up outcomes of 3D and 2D laparoscopic colectomy. Patients and Methods: A total of 91 consecutive patients who underwent either 3D or 2D laparoscopy colectomy from October 2015 to November 2017 by a single surgical team for colon cancer were enrolled. Data were collected from a prospectively constructed database, including clinico-pathological features and operative parameters. The pathological results, recurrence, survival and systemic treatment were collected from the Taiwan Cancer Database. Results: There were 47 patients in the 3D group and 44 in the 2D group. There were no significant differences in characteristics of patients, operation data, pathological results, complications, operative time, blood loss or the number of lymph node harvested between the two groups. In addition, disease-free survival and overall survival were equal between the two groups. Conclusions: This is the first long-term result of a 3D laparoscopic colectomy. In our 3-year follow-up, there was no difference in long-term outcomes between 2D and 3D laparoscopy for colorectal surgery in an experienced centre.

Factors Related to Frailty in Older Cancer Patients Undergoing Colorectal Surgery: A Longitudinal Study.

BACKGROUND: Frailty is common in older cancer patients undergoing colorectal surgery, but few studies have focused on frailty and its associations in this population. OBJECTIVE: The aim of this study was to investigate the prevalence of frailty and its associations in older cancer patients undergoing colorectal surgery. METHODS: A convenience sample of 88 cancer patients 60 years or older undergoing colorectal surgery was recruited from 1 medical center. Frailty, physical activity, functional status, anxiety, depression, and social support of the patients were assessed before surgery, at discharge post surgery, and at 1 month post surgery. RESULTS: The prevalence of frailty in cancer patients undergoing colorectal surgery was 22.7% before surgery, decreased to 19.3% before discharge, and was 12.7% at 1 month after surgery. The proportion of prefrail patients significantly increased from 47.7% before surgery to 71.1% before discharge and was 64.6% at 1 month after surgery. Frail patients were more likely to be older and unmarried, have a lower albumin level, have lower physical activity, and be more dependent on others than nonfrail patients. CONCLUSION: Older cancer patients undergoing colorectal surgery were more likely to be prefrail after surgery than before surgery. Assessment of frailty and its associated factors is necessary for older cancer patients undergoing colorectal surgery before and after surgery. IMPLICATIONS FOR PRACTICE: Frailty may occur in cancer patients after colorectal surgery and is related to malnutrition and low physical activity. Appropriate discharge planning with physical activity tracking and an appropriate diet is encouraged to prevent frailty in cancer patients after colorectal surgery.

Robotic or transanal total mesorectal excision (TaTME) approach for rectal cancer, how about both? Feasibility and outcomes from a single institution.

Laparoscopic surgery for rectal cancer is technically challenging. Robotic and transanal TME (TaTME) are both novel approaches developed to provide better visualization and dissection. We aim to combine both approaches in a hybrid procedure and evaluate the feasibility as well as patient and oncological outcomes in this study. A review of a prospectively maintained database of patients who underwent a hybrid abdominal robotic approach with TaTME for rectal cancer between January 2016 and October 2018 was undertaken. Patient demographics, tumor characteristics and surgical outcomes were recorded and analyzed. A total of 69 patients (43 males, 26 females) received this hybrid approach. Their median age was 58 years (range 35-87) with a mean BMI of 24.3 kg/m2 (range 16.4-44.2). Median distance from anal verge was 5 cm (range 2-9). The patients had a median hospital length of stay of 7 days (range 5-28). Complication rate was 17.4% (12 patients) with 3 patients (4.3%) requiring a reoperation. TME quality was optimal with all of them either complete (81.2%) or almost complete (18.8%). 65 patients (94.2%) had an R0 resection with 4 patients (5.8%) with involved circumferential resection margins (≤ 1 mm). The median number of lymph nodes harvested was 20 (range 6-37). After a median follow-up of 27.7 months (range 7-42), local recurrence was identified in 2 patients (4%). Three patients (5.2%) had distant recurrence at the 3-year mark. Hybrid robotic abdominal dissection with transanal TME for rectal cancer appears to be feasible with comparable surgical outcomes to other traditional approaches.

A Rehabilitation-Based Multidisciplinary Care Model Reduces Hip Fracture Mortality in Older Adults.

PURPOSE: In older adults, the one-year mortality rate after experiencing a hip fracture ranges between 8% and 36%. The purpose of this study was to look at the efficacy of rehabilitation-based multidisciplinary care for older individuals who had hip fractures. PATIENTS AND METHODS: The study included 185 people (aged 65 and over) with a history of hip fracture surgery between February 2014 and March 2017. A survey was conducted one month and six months following the operation to assess the recovery of 93 individuals who were part of a rehabilitation-based multidisciplinary care program and 92 patients who were getting standard therapy with surgery and unsupervised physical therapy. RESULTS: Physical activity, gait, balance evaluation, and depression scale ratings all had statistical significance (P < 0.05) after participants received rehabilitation-based care services from multidisciplinary medical professionals. Furthermore, the refracture and one-year mortality rates in this rehabilitation-based multidisciplinary care model were lower than in the groups getting standard therapy. CONCLUSION: The research indicates the efficacy of a multidisciplinary rehabilitation strategy provided by a collaborative medical team to older individuals with hip fractures.

Preference criteria for regorafenib in treating refractory metastatic colorectal cancer are the small tumor burden, slow growth and poor/scanty spread.

Given the unclear preference criteria for regorafenib in treating refractory metastatic colorectal cancer (mCRC), this study aimed to construct an algorithm in selecting right patients for regorafenib. This was a multicenter retrospective cohort study. Patients with pathology confirmed mCRC and administered with regorafenib for > 3 weeks were enrolled. Patients with good response were defined to have progression-free survival (PFS) of ≥ 4 months. The Kaplan-Meier plot was used to analyze survival. A Cox proportional hazards model was used to analyze univariate and multivariate prognostic factors and was visualized using forest plot. A clustering heatmap was used to classify patients according to responses. The decision tree and nomogram were used to construct the approaching algorithm. A total of 613 patients was analyzed. The median PFS and overall survival (OS) were 2.7 and 10.6 months, respectively. The partial response and stable disease rate are 2.4% and 36.4%. The interval between metastasis (M1) and regorafenib, metastatic status (number, liver, and brain), and CEA level were independent prognostics factors of PFS that classifies patients into three groups: good, bad and modest-1/modest-2 group with PFS > = 4 months rates of 51%, 20%, 39% and 30%, respectively. Results were used to develop the decision tree and nomogram for approaching patients indicated with regorafenib. The preference criteria for regorafenib in treating patients with refractory mCRC are small tumor burden (CEA), slow growth (interval between metastasis and regorafenib) and poor/scanty spread (metastatic status: number and sites of metastasis): The 3S rules.TRIAL registration ClinicalTrials.gov Identifier: NCT03829852; Date of first registration (February 11, 2019).

Insulin-Like Growth Factor 2 mRNA-Binding Protein 1 (IGF2BP1) Is a Prognostic Biomarker and Associated with Chemotherapy Responsiveness in Colorectal Cancer.

Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is an RNA-binding protein and serves as a post-transcriptional fine-tuner regulating the expression of mRNA targets. However, the clinicopathological roles of IGF2BP1 in colorectal cancer (CRC) remains limited. Thus, we aimed to elucidate the clinical significance and biomarker potentials of IGF2BP1 in CRC. A total of 266 specimens from two sets of CRC patients were collected. IGF2BP1 expression was studied by immunohistochemical (IHC) staining. The Kaplan-Meier survival plot and a log-rank test were used for survival analysis. The Cox proportional hazards model was applied to determine the survival impact of IGF2BP1. Public datasets sets from The Cancer Genome Atlas (TCGA) and Human Cancer Metastasis Database (HCMDB), receiver operating characteristic (ROC) plotter, and two CRC cell lines, HCT-116 and DLD-1, were used for validating our findings. We showed that IGF2BP1 was overexpressed in tumor specimens compared to 13 paired normal parts by examining the immunoreactivity of IGF2BP1 (p = 0.045). The increased expression of IGF2BP1 in primary tumor parts was observed regardless of metastatic status (p < 0.001) in HCMDB analysis. IGF2BP1 expression was significantly associated with young age (59.6% vs. 46.7%, p-value = 0.043) and advanced stage (61.3% vs. 40.0%, p-value = 0.001). After controlling for confounding factors, IGF2BP1 remained an independent prognostic factor (HR = 1.705, p-value = 0.005). TCGA datasets analysis indicated that high IGF2BP1 expression showed a lower 5-year survival rate (58% vs. 65%) in CRC patients. The increased expression of IGF2BP1 in chemotherapy non-responder rectal cancer patients was observed using a ROC plotter. Overexpression of IGF2BP1 promoted the colony-forming capacity and 5-fluorouracil and etoposide resistance in CRC cells. Here, IGF2BP1 was an independent poor prognostic marker in CRC patients and contributed to aggressive phenotypes in CRC cell lines.

High concordance of mutation patterns in 10 common mutated genes between tumor tissue and cell-free DNA in metastatic colorectal cancer.

The concordance of mutation patterns between cell-free DNA (cfDNA) and tumor DNA varies in colorectal cancers (CRCs). Next-generation sequencing (NGS) by targeted sequencing can detect novel genes. We aimed to use NGS to test the concordance between cfDNA and tumor DNA in metastatic CRCs. A total of 95 paired tumor and peripheral blood samples from metastatic CRC patients were included. The tumor DNA and cfDNA were analyzed with a 10-gene NGS panel (Illumina HiSeq2500 system). The median number of mutations in tumor samples was 3 (range 0-7). The most commonly mutated gene was TP53 (63.2%), followed by APC (49.5%), KRAS (35.8%) and FAT4 (15.8%). The concordance of mutation patterns in these 10 genes was as high as 91% between cfDNA and tumor samples in these metastatic CRC patients. A sensitivity of 88.2% and specificity of 100% was found when using KRAS mutation status of cfDNA to predict KRAS mutation in tumor tissue. For tumor DNA with TP53, KRAS, or APC mutations, right-sided CRCs were more likely to develop peritoneal metastases, while for tumor DNA with TP53 mutations, left-sided tumors were more likely to have lung metastases. For cfDNA with TP53 or KRAS mutations, right-sided CRCs were more likely to have peritoneal metastases. Due to the high concordance of mutation patterns between cfDNA and tumor samples, monitoring the mutation pattern of cfDNA may be applicable in the treatment of metastatic CRC.

The efficacy of anti-EGFR therapy in treating metastatic colorectal cancer differs between the middle/low rectum and the left-sided colon.

BACKGROUND: Clinically, metastatic rectal cancer has been considered a subset of left-sided colon cancer. However, heterogeneity has been proposed to exist between high and middle/low rectal cancers. We aimed to examine the efficacy of anti-epidermal growth factor receptor (EGFR) treatment for middle/low rectal and left-sided colon cancers. METHODS: This study enrolled 609 patients with metastatic colorectal cancer who were treated with anti-EGFR therapy. They were divided into groups based on primary tumour locations: the right-sided colon, the left-sided colon or the middle/low rectum. The efficacy of first-line and non-first-line anti-EGFR treatment was analysed. Genomic differences in colorectal cancer data from The Cancer Genome Atlas (TCGA) were investigated and visualised with OncoPrint and a clustered heatmap. RESULTS: On first-line anti-EGFR treatment, patients with middle/low rectal tumours had significantly lower progression-free survival, overall survival, and overall response rates (6.8 months, 27.8 months and 43%, respectively) than those with left-sided colon cancer (10.1 months, 38.3 months and 66%, respectively). Similar outcomes were also identified on non-first-line anti-EGFR treatment. In TCGA analysis, rectal tumours displayed genetic heterogeneity and shared features with both left- and right-sided colon cancer. CONCLUSIONS: Anti-EGFR treatment has lower efficacy in metastatic middle/low rectal cancer than in left-sided colon cancer.

Acrolein contributes to human colorectal tumorigenesis through the activation of RAS-MAPK pathway.

Colorectal cancer (CRC) is one of the most well-known malignancies with high prevalence and poor 5-year survival. Previous studies have demonstrated that a high-fat diet (HFD) is capable of increasing the odds of developing CRC. Acrolein, an IARC group 2A carcinogen, can be formed from carbohydrates, vegetable oils, animal fats, and amino acids through the Maillard reaction during the preparation of foods. Consequently, humans are at risk of acrolein exposure through the consumption of foods rich in fat. However, whether acrolein contributes to HFD-induced CRC has not been determined. In this study, we found that acrolein induced oncogenic transformation, including faster cell cycling, proliferation, soft agar formation, sphere formation and cell migration, in NIH/3T3 cells. Using xenograft tumorigenicity assays, the acrolein-transformed NIH/3T3 clone formed tumors. In addition, cDNA microarray and bioinformatics studies by Ingenuity Pathway Analysis pointed to the fact that RAS/MAPK pathway was activated in acrolein-transformed clones that contributed to colon tumorigenesis. Furthermore, acrolein-induced DNA damages (Acr-dG adducts) were higher in CRC tumor tissues than in normal epithelial cells in CRC patients. Notably, CRC patients with higher levels of Acr-dG adducts appeared to have better prognosis. The results of this study demonstrate for the first time that acrolein is important in oncogenic transformation through activation of the RAS/MAPK signaling pathway, contributing to colon tumorigenesis.